This proposal is a continuation of 15 years' of research with the goal to understand the pathophysiology of myocardial ischemia and reperfusion (I/R) particularly as it applies to myocardial protection. It has become evident that coronary endothelium is a critical component in maintaining normal myocardial function. Endothelial cells play a significant role in preventing and exasperating injury related to ischemia and reperfusion. Multiple factors need to be studied including nitric oxide, prostacyclin, endothelin and angiotensin-II. Attempts will be made to understand the interaction of the beneficial and toxic factors. The models to be used to study these intracellular-generated endogenous factors will include rat and swine heart models. These factors will be studied during both global and regional ischemia/reperfusion. The regulatory mechanisms will be studied with particular attention to calcium flux. The approach will be clinically oriented toward cardiac surgery for ischemia involving the territory of the left anterior descending artery.